Faster cross‐bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation

Key points The R403Q mutation, located in the S1 domain of the β‐myosin heavy chain, is associated with a severe phenotype of hypertrophic cardiomyopathy (HCM). Increased cross‐bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of sarcomeric tension generation; however, direct evidence is absent. We studied the relationship between cross‐bridge kinetics and energetics in single cardiac myofibrils and multicellular cardiac muscle strips in human HCM tissue with and without the R403Q mutation. In human HCM with the R403Q mutation, cross‐bridge relaxation was faster and correlated well with a rise in energetic cost of tension generation. Our data suggest that an increase in tension cost is one of the causes underlying cardiomyopathy development in patients with the R403Q mutation. Abstract The first mutation associated with hypertrophic cardiomyopathy (HCM) is the R403Q mutation in the gene encoding β‐myosin heavy chain (β‐MyHC). R403Q locates in the globular head of myosin (S1), responsible for interaction with actin, and thus motor function of myosin. Increased cross‐bridge relaxation kinetics caused by the R403Q mutation might underlie increased energetic cost of tension generation; however, direct evidence is absent. Here we studied to what extent cross‐bridge kinetics and energetics are related in single cardiac myofibrils and multicellular cardiac muscle strips of three HCM patients with the R403Q mutation and nine sarcomere mutation‐negative HCM patients (HCM smn ). Expression of R403Q was on average 41 ± 4% of total MYH7 mRNA. Cross‐bridge slow relaxation kinetics in single R403Q myofibrils was significantly higher ( P < 0.0001) than in HCM smn myofibrils (0.47 ± 0.02 and 0.30 ± 0.02 s −1 , respectively). Moreover, compared to HCM smn , tension cost was significantly higher in the muscle strips of the three R403Q patients (2.93 ± 0.25 and 1.78 ± 0.10 μmol l –1 s −1 kN −1 m −2 , respectively) which showed a positive linear correlation with relaxation kinetics in the corresponding myofibril preparations. This correlation suggests that faster cross‐bridge relaxation kinetics results in an increase in energetic cost of tension generation in human HCM with the R403Q mutation compared to HCM smn . Therefore, increased tension cost might contribute to HCM disease in patients carrying the R403Q mutation.